There were more than 225 million cases of malaria in 2009, with approximately 781,000 people dying that year. There is a great need for a malaria vaccine, and for new treatments-9-15% of those with malaria die despite our best therapies. Over the past 17 years, we have methodically and clearly demonstrated that nitric oxide (NO) is protective against the development of severe malaria and death in humans with malaria. We have shown: (i) patients with clinical malaria have reduced NO production, (ii) polymorphisms in the NO synthase 2 (NOS2) gene that modify NO production and protect against clinical malaria, (iii) markedly low levels of the NOS substrate arginine that correlate with low level NO production, (iv) and endothelial dysfunction that correlates closely with malaria severity and low arginine and low NO levels. We have also established that (v) administration of intravenous arginine to adults with moderately severe malaria is safe and that it corrects hypoargininemia, low NO levels, and endothelial dysfunction. Based on results of our studies, we have proposed that improving NO levels and NO bioavailability will be a safe and effective adjunctive treatment for humans with malaria. This is a grant in which we will carefully plan for an application for a U01 grant to perform the following aims: Determine the safety, pharmacokinetics, and pharmacodynamics of intravenous arginine in (1A) children with moderately severe malaria and (1B) children with severe malaria; and Determine the safety, pharmacokinetics, and pharmacodynamics of intravenous nitrite in (A) adults with moderately severe malaria and (B) adults with severe malaria. The arginine and nitrite will be given in addition to standard antibiotc and supportive treatment of the malaria. Measured outcomes will be patient safety, arginine and nitrite pharmacokinetics, NO production, parasitemia, angiopoietin 2 levels, and endothelial function. In severe malaria patients, we will also measure lactate clearance, coma recovery time, and survival. Aim 1 studies will be done with children at the Hubert Kairuki Memorial University (HKMU) in Dar es Salaam, Tanzania; Aim 2 studies will be done with adults at the Queen Elizabeth Hospital in Sabah, Malaysian Borneo. Our Research team is already in place with excellent established site infrastructure and staff in both Tanzania and Malaysia. During this one year planning grant, we will (a) identify the research team/sites; (b) design the study; develop (c) the clinical protocol; (d) the data analysis and (e) statistical management & analysis plans; (f) the informed consent forms; (g) the investigator's brochure; (h) a manual of operations; (i) a data sharing plan; (j) milestones; (k) plans for acquisition and administration of study agents; (l) plans for acquisition of a US Food and Drug Administration (FDA) investigational new drug (IND) certificate for nitrite; (m) a data and safety monitoring plan; (n) a detailed budget fo design of the study; (o) a detailed budget for performance of the clinical trial, including a budge for preparation of a final study report; and (p) training materials for study staff. PUBLIC HEALTH RELEVANCE: There were more than 225 million malaria cases in 2009, with approximately 781,000 malaria deaths. There is no effective vaccine for this disease, and despite recent improvements in treatment, 9 to 15% of malaria patients die. Adjunctive treatments have not been beneficial. There is a great need for new treatments. Our studies indicate that increasing arginine may be a useful adjunctive therapy. The studies for which we plan here will answer important questions relative to the pathophysiology of severe malaria regarding arginine, nitrite, and nitric oxide, and they may lead to use of an adjunctive therapy such as arginine or nitrite that would reduce morbidity and mortality caused by malaria infection.